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Upstream open reading frame translation enhances immunogenic peptide presentation in mitotically arrested cancer cells

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canoni...

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Main Authors: Kowar, Alexander (Author) , Becker, Jonas Philipp (Author) , Pizzo, Rossella del (Author) , Tang, Zhiwei (Author) , Champagne, Julien (Author) , Wellach, Kathrin (Author) , Samimi, Kiana (Author) , Galindo-Albarrán, Ariel (Author) , Körner, Pierre-René (Author) , Montenegro Navarro, Jasmine (Author) , Elía, Andrés (Author) , Tilghman, Fiona Megan (Author) , Sakeer, Hanan (Author) , Mendoza-Parra, Marco Antonio (Author) , Riemer, Angelika (Author) , Agami, Reuven (Author) , Loayza-Puch, Fabricio (Author)
Format: Article (Journal)
Language:English
Published: 27 August 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-15
ISSN:2041-1723
DOI:10.1038/s41467-025-63405-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-63405-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-63405-2
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Author Notes:Alexander Kowar, Jonas P. Becker, Rossella Del Pizzo, Zhiwei Tang, Julien Champagne, Kathrin Wellach, Kiana Samimi, Ariel Galindo-Albarrán, Pierre-René Körner, Jasmine Montenegro Navarro, Andrés Elía, Fiona Megan Tilghman, Hanan Sakeer, Marco Antonio Mendoza-Parra, Angelika B. Riemer, Reuven Agami, and Fabricio Loayza-Puch
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Summary:Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5′ untranslated region (5′ UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.
Item Description:Gesehen am 03.02.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-63405-2

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